The molecular structure of the complex capsid of adenovirus will be investigated at high resolution by an X-ray crystallographic analysis of its major constituent, the coat protein hexon (Mr 3 x 109,058). A model for the placement of the 240 hexons within the capsid, derived using electron microscopy, will be used to orient the individual molecules. This approach will yield atomic coordinates for the greater part of the outer capsid, and for 60% of the total protein in the virion. Further information on other structural proteins can then be related to this framework. The structure determination of hexon, in progress at 2.9 angstroms resolution, will complete the definition of the 967 amino acid chain and its correlation with the chemical sequence. A detailed molecular model, to atomic resolution, will be derived from model-building using computer graphics, followed by restrained least-squares structure refinement. The diffraction data will be extended to the resolution limit of approximately 2.0 angstroms using the Cornell High Energy Synchrotron Source (CHESS). The structure of the immunologically distinct type 5 hexon, for which isomorphous crytals are at hand, will also be determined. Comparison of the structures will reveal the basis for the immunological differences between hexons type 2 and 5. Extension to other types would reveal the differentiation of the viral coat, and indicate the reason for the variable stability of the adenovirus capsid. Definition of the immunologically significant sites on hexon, corresponding to the major antigenic determinants of adenovirus, will indicate relevant peptides, which could provide synthetic vaccines against adenoviral infections in both humans and domestic animals. Purified hexon has already been shown to confer immunity when used in place of the complete virus, the use of which has discontinued due to its potential oncogenicity. The investigation will reveal the manner in which the geometry of hexon permits different chemical bonding to occur at each of the four independent locations within the capsid. The detailed amino-acid side-chain interactions will indicate the structural basis for these discrete states. The adenovirus capsid will serve as a model for mammalian viruses in general. A full understanding of adenovirus is not only of intrinsic interest, but will also indicate the extent to which complex systems may be studied by integrating detailed pictures of their component molecules.